Treatment-Resistant Depression
Treatment resistance has been variably defined but typically involves the persistence of a significant depression despite two or more adequate therapeutic trials
(20). In this context, there are several issues to consider, including
Obtaining this information is critical, since a substantial proportion of patients may experience
poor response due to a variety of factors other than true treatment resistance.
Accurate Diagnosis. Incorrect diagnosis is a common cause for nonresponse to antidepressants. An important issue involves misdiagnosis of the depressive episode as unipolar major depression when the underlying condition is bipolar disorder (particularly type II). In this context, antidepressant-induced “misadventures” may include poor response, worsening of certain symptoms (e.g., agitation, anxiety), or switching into hypomania/mania.
Degree of Resistance. A related question is the degree of treatment resistance. In this context, a number of staging methods are published with the three most frequently employed, including
-
Increased resistance is determined by
successive failures of various antidepressants and electroconvulsive therapy (ECT)
(21)
-
Distinguishing across
a continuum from nonresponse, treatment resistance, and chronic resistant depression
(22)
-
Consideration of both the
number of failed trials and the optimization of each attempt
(23)
Comorbidities. Another important factor is the frequency of comorbid conditions which can complicate and compromise adequate response. Disorders that frequently co-occur with major depression include
-
Anxiety and sleep-related disorders
-
Alcohol and other substance use disorders
-
Pain syndromes
-
Axis II disorders
-
Attention-deficit hyperactivity disorder (ADHD)
In addition, more recent data indicate that comorbid
social anxiety disorder may predispose to depression recurrence
(24).
Associated Symptoms. An important diagnostic issue is
psychotic depression (25). Symptoms of psychosis in the context of depression are often subtle and unrecognized. The presence of such symptoms, however, usually predicts a poor response to antidepressant monotherapy as well as an increase in morbidity and mortality
(26). Further,
melancholic features (e.g., pervasive anhedonia, mood reactivity, psychomotor changes) occur in up to 25% of patients with MDD and may be associated with reduced remission rates, particularly with a selective serotonin reuptake inhibitor (SSRI)
(27).
Adequate Treatment Trial. An adequate antidepressant trial may be compromised by
subtherapeutic doses. For example, one study
(28) found that 60% of elderly depressed patients did not receive antidepressants while in the hospital or on outpatient follow-up (median interval of 45 weeks). Furthermore, most who did receive an antidepressant were usually given inadequate doses.
Time on treatment is another issue. Even though patients can show improvement in 2 to 3 weeks, some may require up to 14 weeks before an adequate response occurs. If, however, there has not been at least partial benefit in 3 to 4 weeks, we recommend pursuing an alternate strategy.
Adherence to Treatment. Nonadherence with the medication regimen is an important factor. A substantial percentage of patients will not sufficiently adhere to treatment, particularly over longer continuation and maintenance periods (
29,
30 and
31). For certain antidepressants, therapeutic drug monitoring (TDM) can be useful to confirm suspected poor adherence, which the physician can then address with the patient (please see “
Adherence” section in
Chapter 3).
Level of Recovery. Based on the NIMHsponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study, approximately 70% of patients with MDD did not experience a remission after an aggressive trial with citalopram and required additional interventions
(32). The implications of unremitted MDD are significant, with over 50% of completed suicides involving a MDE. In addition, a prolonged episode usually has a negative impact on family and other social support systems, career and general health
(33). Conversely, significant
psychosocial stressors not addressed can contribute to persistent depressive symptomatology despite adequate pharmacological intervention. In such situations, supportive, interpersonal, and cognitive behavioral therapy may be necessary adjuncts to medication. Treatment approaches for inadequate response are discussed in more detail in
Chapter 7.
Functional Status and Quality of Life. Increasingly, the focus of effectiveness is shifting from response to remission to recovery. This last issue attempts to translate reduction in symptoms to improved psychosocial interactions and greater satisfaction in life activities (
34,
35).